ABSTRACT / PROJECT SUMMARY Wet age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. Anti-VEGF therapy is currently the gold standard for wet AMD treatment. However, up to 50% of patients in the long term have a suboptimal response to anti-VEGF therapy. A better alternative method for treatment of AMD is urgently needed. We have recently invented a novel, effective, and highly-selective anti- vascular therapy, termed ?photo-mediated ultrasound therapy (PUT)?. PUT is based on microcavitations in microvessels produced by synergistically applied laser pulses and ultrasound bursts. As demonstrated by our preliminary studies on clinically relevant animal models, PUT is capable of eliminating the target microvessels in the choroid without causing unwanted damage to the surround tissue, facilitating optimal treatment outcome for patients with AMD. The ultimate goal of our research is to develop and commercialize a new, noninvasive therapeutic technique for safe and efficient treatment of choroidal neovascularization (CNV) in patients with wet AMD. To achieve the ultimate goal, the project streamlines to achieve the technological transition, including the following milestones: (1) to build and verify the Phase I ?-prototype on rabbit eye models, (2) to build and verify the Phase II ?- prototype for human subjects, (3) to complete clinical studies, and (4) to define the approval pathway with the FDA. In this Phase I research, PhotoSonoX LLC, via an established collaboration with the Kellogg Eye Center at the University of Michigan School of Medicine, will build a clinically ready ?-prototype system, and fully test its safety and efficacy to pave the road to clinical studies in Phase II. The hypothesis of the Phase I study is that PUT can precisely remove pathologic microvessels in the eye without causing short-term and long-term damage in the surrounding tissue. To test this hypothesis, the following specific aims will be accomplished: Aim 1. Develop a clinically ready ?-prototype PUT system which has a reasonable cost and can be tested on clinically relevant rabbit eyes in Phase I and on human eyes in Phase II. Aim 2. Determine the long-term safety of PUT for treatment of choroidal microvessels on normal rabbits in vivo. Aim 3. Validate the short and long-term efficacy and safety of PUT for treating pathologic choroidal neovascularization in vivo on a rabbit model of AMD. The outcome from this research will be proof- of-concept that the PUT effectively and safely removes pathologic choroidal microvessels to treat AMD. We expect that the proposed PUT device has great potential to transform our care of patients with AMD by facilitating targeted and precise therapy while reducing the treatment burden and side effects.